Neovastat (Æ-941) in refractory renal cell carcinoma patients: report of a phase II trial with two dose levels

Batist, Gerald; Patenaude, François; Champagne, Pierre; Croteau, David; Levinton, Carey; Hariton, C.; Escudier, Bernard; Dupont, Éric

doi:10.1093/annonc/mdf195

Cited by 89 publications

(34 citation statements)

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“…Furthermore, treatment of patients (n = 44) with recurrent and progressive glioblastoma multiforme with a combination of marimastat and an alkylating agent temozolomide resulted in increased progression-free survival at the time point of 6 months (34). In a small group of patients with advanced renal cell carcinoma, treatment with a higher dose of neovastat was associated with longer survival than treatment with a lower dose (35).…”

Section: Discussionmentioning

confidence: 91%

High Serum Levels of Matrix Metalloproteinase-9 and Matrix Metalloproteinase-1 Are Associated with Rapid Progression in Patients with Metastatic Melanoma

Nikkola

Vihinen

Vuoristo

et al. 2005

Clinical Cancer Research

171

127

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Purpose: Matrix metalloproteinases (MMP) are proteolytic enzymes that play an important role in various aspects of cancer progression. In the present work, we have studied the prognostic significance of serum levels of gelatinase B (MMP-9), collagenase-1 (MMP-1), and collagenase-3 (MMP-13) in patients with advanced melanoma. Experimental Design: Total pretreatment serum levels of MMP-9 in 71patients and MMP-1and MMP-13 in 48 patients were determined by an assay system based on ELISA. Total MMP levels were also assessed in eight healthy controls. The active and latent forms of MMPs were defined by usingWestern blot analysis and gelatin zymography. Results: Patients with high serum levels of MMP-9 (z376.6 ng/mL; n = 19) had significantly poorer overall survival (OS) than patients with lower serum MMP-9 levels (n = 52; median OS, 29.1 versus 45.2 months; P = 0.033). High MMP-9 levels were also associated with visceral or bone metastasis (P = 0.027), elevated serum alkaline phosphatase level (P = 0.0009), and presence of liver metastases (P = 0.032). Serum levels of MMP-1and MMP-13 did not correlate with OS. MMP-1 and MMP-9 were found mainly in latent forms in serum, whereas the majority of MMP-13 in serum was active (48 kDa) form. MMP-13 was found more often in active form in patients (mean, 99% of the total MMP-13 level) than in controls (mean, 84% of the total MMP-13 level; P < 0.0001). After initiating the therapy, patients with elevated levels of MMP-1 (z29.8 ng/mL, n = 10) progressed more rapidly than patients with lower levels (median, 1.9 versus 3.5 months; P = 0.023). Serum levels of MMP-9 and MMP-13 did not correlate with the time to progression (TTP). In multivariate analysis with age and gender, MMP-9 or MMP-1turned out to be independent prognostic factors for OS [P = 0.039; hazard ratio (HR), 1.8; 95% confidence interval (95% CI), 1.03-3.3] or TTP (P = 0.023; HR, 2.7; 95% CI, 1.15-6.4), respectively. Conclusions: Our findings provide evidence that MMP-1, MMP-9, and MMP-13 play important roles at different phases of metastatic melanoma spread and that serum MMP-9, in particular, could have clinical value in identifying patients at high risk for melanoma progression.

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Section: Discussionmentioning

confidence: 91%

High Serum Levels of Matrix Metalloproteinase-9 and Matrix Metalloproteinase-1 Are Associated with Rapid Progression in Patients with Metastatic Melanoma

Nikkola

Vihinen

Vuoristo

et al. 2005

Clinical Cancer Research

171

127

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“…A phase I/II trial of shark cartilage found no clinical benefit [52]. Neovastat, another cartilage extract, was associated with a survival benefit in renal cell carcinoma in higher versus lower doses [53]. However, that trial was not randomized.…”

Section: Biologic Treatmentsmentioning

confidence: 99%

Complementary and Alternative Therapies for Cancer

2004

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“…A phase-I trial of AE-941 was performed in 144 patients with refractory solid tumors, including patients with metastatic RCC. As shown on Table II, treatment with AE-941 (either an escalated or high single dose), resulted in an objective response in a mere 14% of patients [Batist et al, 2002].…”

Section: Targeting Angiogenesis In Rcc: Therapeutic Outcomes and Clinmentioning

confidence: 97%

“…AE-941 (Neovastat) is a pure shark cartilage compound that selectively inhibits −2, −9, and −12 and competes for the binding of VEGF to its receptor (VEGFR-2), resulting in endothelial cell apoptosis [Batist et al, 2002]. A phase-I trial of AE-941 was performed in 144 patients with refractory solid tumors, including patients with metastatic RCC.…”

Section: Targeting Angiogenesis In Rcc: Therapeutic Outcomes and Clinmentioning

confidence: 99%

Targeting vasculature in urologic tumors: Mechanistic and therapeutic significance

Sakamoto

Ryan

Kyprianou

2007

J of Cellular Biochemistry

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Recent advances toward understanding the molecular mechanisms regulating cancer initiation and progression provide new insights into the therapeutic value of targeting tumor vascularity by interfering with angiogenic signaling pathways. The functional contribution of key angiogenic factors toward increased vascularity characterizing metastatic tumors and their therapeutic exploitation is considered in three major urologic malignancies, renal, bladder, and prostate cancer. With the realization that the success of the therapeutic efficacy of the various anti-angiogenic approaches for the treatment of urologic tumors has yet to be proven clinically, the challenge remains to select critical angiogenesis pathways that can be targeted for an individual tumor. Here we discuss the major mechanisms that support formation of vasculature in renal, bladder, and prostate tumors and the current results of targeting of specific molecules/regulators for therapeutic intervention against metastastic disease. Keywordsvascularity; tumor growth; apoptosis; VEGF; bladder cancer; renal cancer; prostate cancer In 2007, there will be an estimated 346,440 new cases diagnosed with urologic cancer in the United States and 54,360 Americans will die from a urologic malignancy (SEER Cancer Statistics Review, http://cancernet.nci.nih.gov/statistics). This mortality rate is alarmingly high as it translates to one individual dying every 9 min in the US due to a urologic tumor and thus a significant health issue.Angiogenesis is an essential process in normal physiological functions such as ovarian cycle in female reproductive system [Kaczmarek et al., 2005] and a contributing factor in disease states such as chronic inflammation, arthritis, cancer, and macular degeneration . During the development of the embryo, mesoderm differentiates into angioblasts; these endothelial cells, not yet organized into a lumen, form primitive vessels toward development of blood vessel network, via vasculogenesis. In the adult, new blood vessels form from preexisting vasculature, via angiogenesis [Risau, 1997], while malignant conditions induce a hypercoagulable state in their hosts [Nash et al., 2001]. By early 1960s it was evident that tumors could elaborate diffusible substances that induce angiogenesis from the host vasculature [Algira et al., 1945;Greenblatt and Shubick, 1968]. The increased tumor vascularity was originally believed to be vasodilation of the host endothelium in response to metabolic waste products from within the tumor . A decade later Dr. Folkman's pioneering work identified angiogenesis as a required phenomenon for tumor growth and metastasis, first defining the potential therapeutic value of agents targeting this process , 1971]. Tumor blood vessels exhibit characteristic markers which are not present in normal angiogenic tissues . After enduring the circulation "journey," metastatic cancer cells can escape out of the endothelial vasculature and in the target tissue via extravasation. How do the metastastic cells signal activa...

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Neovastat (Æ-941) in refractory renal cell carcinoma patients: report of a phase II trial with two dose levels

Abstract: Neovastat is well tolerated by advanced cancer patients at doses of 60 and 240 ml/day. The higher dose of Neovastat administered in this trial is associated with a survival benefit in RCC, which is not explained by differences in major prognostic factors.

Cited by 89 publications

References 10 publications

High Serum Levels of Matrix Metalloproteinase-9 and Matrix Metalloproteinase-1 Are Associated with Rapid Progression in Patients with Metastatic Melanoma

High Serum Levels of Matrix Metalloproteinase-9 and Matrix Metalloproteinase-1 Are Associated with Rapid Progression in Patients with Metastatic Melanoma

Complementary and Alternative Therapies for Cancer

Targeting vasculature in urologic tumors: Mechanistic and therapeutic significance

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